The long term goal of the proposed research is to elucidate the neural mechanisms that control activity of noradrenergic locus coeruleus (LC) neurons. Our previous results have generated important questions concerning (i) functionally diverse inputs to the LC from one of its major afferents, the nucleus paragigantocellularis lateralis (PGi), and (ii) the functional impact of distinct input channels to the nuclear core vs. extranuclear dendrites of LC neurons. The proposed experiments will determine the relative contributions of these different inputs on LC activity as well as on LC output function in target cortical regions. Many types of information must reach the LC to provide for the highly integrative characteristics of impulse activity in these neurons seen in behaving animals. However, we recently found that major afferents to the nuclear core of the LC are restricted to two areas in the rostral medulla, the PGi and the nucleus propositus hypoglossi (PrH). This surprisingly small number of afferents seems inconsistent with the complex activity of LC neurons. One explanation may be that functionally distinct inputs impinge on the LC from the PGi and PrH. This possibility will be tested for the PGi projections in the presently proposed studies. LC neurons have extensive extranuclear dendrites. Our recent studies have revealed that this large postsynaptic surface of LC neurons may receive afferents that are distinct from, but interactive with, those impinging on the nuclear core from the PGi. Two putative dendritic inputs will be examined here in detail, the medial preoptic area (MPO) and the infralimbic prefrontal cortex (PFC). A series of neurophysiological experiments will compare the influence of inputs to the LC core (from the PGi) or LC shell (from the MPO or PFC) on LC activity. In addition, integration in these two channels of inputs will be examined. These will be some of the first studies to manipulate multiple inputs to LC neurons and determine integrative properties of these neurons. Our studies to date have focused upon the anatomy and physiology of LC neurons and their inputs, but the issue of functional influence of afferents on LC targets has not been addressed. Here we will examine the impact of activation of different LC inputs on LC output functions in two cortical measures, sensory threshold in olfactory bulb mitral cells and BEG activation in cerebral cortex and hippocampus. By conducting these studies, we will extend the analysis of afferent regulation of LC neurons to include the full circuit: from afferent, through the LC, to LC target areas. These studies are the next steps in our comprehensive analysis of circuits that control the LC system, extending our investigation to integration of LC inputs and modulation of LC output functions. They will provide the first systematic investigation of inputs to the extranuclear dendrites that characterize LC neurons, the first study of integration of inputs to LC neurons, and the first examination of the effects of LC afferents on LC output functions.